Cerebrotendinous cholestanolosis in relation to other cerebral xanthomatoses

Cerebrotendinous cholestanolosis in relation to other cerebral xanthomatoses

CEREBROTENDINOUS C H O L E S T A N O L O S I S IN R E L A T I O N TO OTHER CEREBRAL XANTHOMATOSES J. G. Y. de Jong*, C. M. van Gent** and J. HI. De...

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CEREBROTENDINOUS

C H O L E S T A N O L O S I S IN R E L A T I O N

TO OTHER CEREBRAL XANTHOMATOSES

J. G. Y. de Jong*, C. M. van Gent** and J. HI. Delleman*

SUMMARY A synopsis is given of 37 reported patients with cerebrotendinous xanthomatosis; divided in I I possible, but not proven cases of C.T.Ch. (cerebrotendinous cholestanolosis), and 26 proven cases. An increased content of cholestanol in serum or tissue, was used as the main criterion. The ophthalmological and neurological signs are tabulated. Attention is drawn to the fact that cholestanol is not mentioned in the extensive literature on related diseases with possible cerebrospinal xanthomas, such as eosinophilic granulomatosis and hyperlipoprotcinemia. The importance of a possible role of cholestanol in these diseases is stressed. A hypothetical form of cerebrotendinous cholesterolosis is discussed. A family with a sibship of parents and twelve children, three of which showed C.T.Ch. is described. The development of the clinical picture confirmed the variable expression of the autosomal recessive disease. Two patients showed disturbances of steroid metabolism. A first contribution to the search for linkage with the H.L.A. system is presented. Cholestanol over cholesterol ratio, appeared to be independent of the type of lipoprotein, in search for therapy we found in patients with hyperlipoproteinemia type II A, that cholestyramine alone gave dangerously high blood levels of cholestanol; in combined treatment of cholestyramine with clofibrate cholestanol, levels were comparable to those of the controls. The possibilities of therapy are discussed. C e r e b r o t e n d i n o u s cholestanolosis, is the n a m e given by PHILIPPART a n d VAN BOGAERT (1969) to a disease originally described as c e r e b r o t e n d i n o u s cholesterinosis by VAN

BOGAERT(1937; VAN BOGAERTet al., 1937 a n d 1969). The m o n o g r a p h of VAN BOGAERT et al. (1937) c o n t a i n e d all the relevant signs: a disease starting in childhood with slowly progressive mental, pyramidal and cerebellar signs; later showing progressive swellings of the achilles tendons, hard painless t u m o u r s of the tuberositas tibiae and sometimes nodules of extensor t e n d o n s of several fingers, and cataracts; still later a t r o p h y of muscles a n d b u l b a r signs a n d sometimes disturbances of sensibility. A t a u t o p s y they f o u n d : degeneration of the pyramidal tracts from distal to the level of the cerebral peduncles, a n d of the tracts of GOLL and BURDACH; lOSS Of cells a n d lesion of the arciform systems of the olives a n d degeneration of olivo-cerebellar fibres; disappearance of most of the Purkinje cells; foamy cells and deposits of cholesterol a n d its esters in the white matter of the cerebellum with almost systemic destruction * Department of Ophthalmogenetics of the Netherlands Ophthalmic Research Institute Amsterdam, The Netherlands. ** Gaubius Institute T.N.O. Leiden, The Netherlands. Clin. Neurol. Neurosurg., Vol. 79-4

254 o f the d e n t a t e nuclei; i m p o r t a n t d e p o s i t s o f fats with gliosis w i t h o u t m u c h loss o f fibres a n d cells in the p a l l i d u m ; s e c o n d a r y a t r o p h y o f muscles; i m p o r t a n t d e p o s i t s o f a mixture o f fats a n d cholesterin in several t e n d o n s ; small n o d u l e s o f the p l e u r a and o s t e o p o r o s i s o f certain regions o f the femur. Every clinician is d e p e n d e n t on the b i o c h e m i s t r y o f his time a n d so VAN BOGAERT'S c o l l a b o r a t o r s : EPSTEIN (1936), EPSTEIN a n d LORENZ (1937) a n d EPSTEIN a n d KREITNER (1940) f o u n d the deposits to c o n t a i n cholesterol a n d its esters. U n t i l 1968 several cases o f c e r e b r o t e n d i n o u s cholesterolosis were described. But then MENKESet al. (1968) a n d SCHIMSCHOCK et al. (1968) p u t the diagnosis o f c e r e b r o t e n d i n o u s x a n t h o m a t o s i s on solid g r o u n d , by d e m o n s t r a t i n g t h a t specifically b o t h free a n d esterified 5 a l p h a cholestan-3 b e t h a - o l ( = cholestanol) were present in greater t h a n n o r m a l c o n c e n t r a tions in several areas o f the brain. In their a u t o p s y they confirmed the findings o f VAN BOGAERT with f o a m y cells, m u l t i n u c l e a t e d giant cells a n d needle s h a p e d birefringent crystals. A l s o in their case, the vessels at the base o f the brain did n o t c o n t a i n a t h e r o m a t a , b u t a t h e r o m a t o u s c o r o n a r y heartdisease was present. As the presence o f c h o l e s t a n o l seems to be the m o s t characteristic finding, the diagnosis o f the earlier described patients b e c a m e uncertain, including the p r o b a b l y very first case o f SCHNEIDER (1936). It a p p e a r e d that large a m o u n t s o f c h o l e s t a n o l were still present in the cerebellum o f one o f VAN BOGAERT'S original patients. He k e p t his interest in the x a n t h o m a t o s e s , (1937, 1962). In 1969, VAN BOOAERT c o u l d confirm that the p a t e r n a l cousin o f his first case s h o w e d d e p o s i t s with a large percentage o f cholest a n o l a n d that V.E. the m a t e r n a l a u n t o f his first case, who was m e n t i o n e d in several p u b l i c a t i o n s - VAN BOGAERT et al. (1937), VAN BOGAERT (1962), EPSTEIN a n d LORENZ (1937), EPSTEIN and KREITNER (1940) - did n o t show the picture o f cholestanolosis. She was now described as a m a n i f e s t a t i o n o f cerebral arteriosclerosis in a h y p e r c h o l e s t e r inemic family, which is i m p o r t a n t in regard to the genetics o f the disease. Own patients: Family P 1565 fig. 1. Theprobandus G. F 11 4 born 1940. He has a healthy twin sister. He completed primary school and did unskilled work until 1972. He was rejected as unfit for military service for a heart failure and for tumours under his knees. Hetero-anamnestically, there was a gradual loss of intellectual capacity. He was regularly seen by the neurologist since 1967 and a gradual worsening of the neurological picture was found. In 1967: bald headed, horizontal nystagmus, cataracts, positive snoutreflex and palmomental reflex. Arms: positive Wartenberg reflex, R-sided Mingazzini, R-sided dysdiadochokinesis, abdominal refexes R < L. Legs: hyperreflexia, R-sided Babinski, Rossolimo and Bechterew reflexes, hypalgesia of the legs, bilateral pes excavatus. Gait: He showed pronounced knock knees and walked with a drag in his right leg, whilst his knees and hips were slightly flexed and his body was bent forward. He had hard tumours as half golf balls in the region of the tuberositas tibiae and 7 cm long bananalike tumours of the achilles tendons. All the routine examinations of blood, urine and cerebrospinal fluid were normal. No increase in gonadotropins and the amino acid pattern was normal. LEG : Rather pronounced bilateral disturbances, with hyperventilation, L-sided more theta and delta frequencies. He was known with an insufficiency and slight stenosis of the mitral and aortic valves since 1959. Operation for cataracta corticalis posterior and anterior, resulted in an improvement in vision from 6/30 to 6/5. A diagnosis of cerebrotendinous cholesterinosis was made. The tumours on

255 CEREBROTENDINOUS CHOLESTANOLOSIS

P 1565

~'-~11 112 ~1 ~'-~2~'-~3~4~5~'-~6~"~7i8 ~9 ~'-~10 I-1 d

DISEASED

OQ

PERSONALLY EXAMINED

I~ PROBAND

LEGEND I Fig.1

the tuberositas tibiae were removed and a yellow tissue mass was found. Chemically, it mostly contained cholesterol and cholesterol esters. After Menkes' work the diagnosis was changed to cerebrotendinous xanthomatosis or cholestanolosis. The patient complained of diarrhoea all these years, with loose stools three to four times daily. In 1969 we sent him as a special case to Biemond, who reported the case on a clinical demonstration (1970). The percentage of cephaline, lecithine, sphingomyeline and lysolecithine was found normal in erythrocytes and plasma. Hormonologic examination: There was a disturbance of the synthesis of corticoids in the adrenal cortex. At first large amounts of a substance, which supposed to be corticosteron, were found. (patient F., F II 12). The Karyotype was normal: 46,XY. His I.Q. tested with the WAIS test was 73, calculated from 4 parts of the GIT test, it was 80. Since 1972 he had all the bilateral pathological reflexes of arms and legs and the cerebellar disturbances increased. The vibration sense was lost distally from Th VIII. In 1975 he had a subacute bacterial endocarditis and positive cultures of alpha streptococci. There was an obstructive cardiomyopathy and a normochromic normocytic anemia. His liver was just palpable and his spleen was enlarged a hand's breadth below the costal arch. From that moment he walked very slowly with the aid of two canes until suddenly in August '76 a leftsided hemiplegia developed. His CSF showed 257/3 cells, a gram positive coccus had been cultured. He had a leftsided total hemiplegia, which gradually improved until almost the situation before the stroke.

Patient T. F I I , 8 born 1944. He had a normal development, completed secundary school, qualified as an electrician, but had difficulties in climbing ladders. He works now as a social pedagogue in a youth prison. He took up long distance running at 26, as therapy for his poor equilibrium. Three or four years ago he noticed thickening of the Achilles tendons. In 1974 his vision diminished and he was operated on both eyes for cataract. Since 1972 he has had difficulty with walking. In June 1975 he was psychically alert. His skin showed some seborrhoic redness above the eyes and multiple effiorescences of elbows and knees and the back of the hands; this was diagnosed as psoriasis. He showed nystagmus. He had hyperreflexia of both arms with Hoffmann-Tr6mmner and flexorreflexes positive. His achillestendons showed tumours 11 cm long and 7 cm wide. Hyperreflexia and cloni of the legs with all the pathological reflexes, disturbed vibration sense and pronounced ataxia of the legs and cerebellar gait were all present.

256 Patient F. F I I , 12 born 1950. After a normal partus, he developed well, was early with his landmarks, but when he went to school his development slowed down and it became clear that he was mentally deficient. After 5 years of special school and 2 years in a paedological institute he just managed to read and write and do simple calculations. In '67 he showed some acrocyanosis, positive Wartenberg reflexes of the arms, pes excavatus, and normal reflexes. The Romberg sign was slightly positive and some cerebellar ataxia was noted with walking. In 1970 he was clinically observed. The cerebrospinal fluid showed a slightly increased protein content. An EEG pleaded for diffuse cerebropathy. The plasma cortisol was normal ; the chromatogram showed a spot, thought at first to be cortison, however, two dimensial chromatography disproved this. It could be an largely increased amount of a normal substance, or an abnormal product. In 1974 he had pronounced cerebellar ataxia. The reflex of Rossolimo was strongly positive. In June 1975 he showed hyperreflexia and all of the pathological reflexes of the legs were present. Till now no tendinous tumours have developed. His eyes were found normal in 1967 and by slitlamp examination in 1975, he showed radial cataract. The father, the mother, the brothers and the sisters of the patients showed no relevant abnormalities on repeated examinations; see further the paragraph on cataracts. FIG. 2. Concentrations of cholesterol and cholestanol in bloodsera of family P 1565 Serum nr.

Donor

1 2

Father Mother

4 5 7

non-pat

Age in years

CHOLESTEROL

CHOLESTANOL

mg/dl

mg/dl

% of total sterol

81 72

144 283

0.62 1.39

0.43 0.49

2 3 4

39 37 36

220 177 198

0.97 0.66 0.98

0.44 0.38 0.50

8 10 11 12

5 6 7 8

35 33 31 30

180 221 148 271

0,87 1,03 0.67 1.5

0.49 0.47 0.45 0.39

13 15

9 10

28 38

143 420

0.65 1,20

0.46 0.29

36 32 26

112 208 185

2,67 10.50 14,49

2.38 5.05 7.83

6 9 14 Normal

patient G. F II 4 T. F 1I 8 T. F I1 12

225 + 25

Cholestanol concentrations in mgr/dl as well as in % of total sterol concentration are definitely increased in the three patients. The cholestanol concentrations were determined by gaschromatography after enzymatic conversion by cholesterol oxidase of sterols to their parent ketones. The sera 6, 9 and 14 of our three patients F II, 4, 8, 12 (G.T.F.) show a greatly increased cholestanol content in mgr/dl and a large augmentation of the proportion cholestanol to total cholesterol. Compared to normal ranges the total lipid values are normal or low in the patients and their nonaffected relatives. The same holds for the lipoprotein composition. Lipoprotein composition was determined by ultracentrifugation (UCF) and weighing of the lipids, extracted from the lipoprotein fractions (concentrations in mgr/dl). The ratio of cholestanol over cholesterol was determined in the lipoprotein fractions of each of the 5-UCF fractionated sera. For each serum the ratio cholestanol/ cholesterol was similar in each of the lipoprotein fractions. There is no evidence that a particular lipoprotein is involved in cholestanol transport.

257 riG. 3 Lipoprotein concentrations in lipid values in 2 'normals' and 3 patients of family P 1565 in mg/dl Lipid concentrations in lipoproteins in mg/dl CHYLO

VLDL

LDL

HDL

Total lipid concentration in mg/dl

(nr II) (nr 12)

norm 1 2

5 5

38 170

228 469

143 141

414 785

(nr 6) (nr 9) (nr 14)

patient G. F I I 4 T. F II 8 F. F 1I 12

2 7 5

40 150 118

243 362 289

86 199 160

372 718 572

normal range

5-10

300-450

130-260

700 4- 200

40-180

DIAGNOSISAND DIFFERENTIALDIAGNOSIS: With regard to deposits of cholesterol, cholestanol and related substances in the central nervous system, the following disease entities are important :

I. PRIMARY DISORDERS WITH XANTHOMAS

A. Eoshwphilic Granuloma (The Hand-Schfiller-Christian syndrome)

vaN ~OGAERT et al. (1937) clearly differentiated this syndrome from the C.T.Ch. on clinical and pathological grounds. LICHTENSTEIN(1953) considered this syndrome, together with the one of Letterer-Siwe and the eosinophilic granuloma to belong to one disease entity: The 'histiocytosis X.' This concept was criticized by several authors; L1EBERMANet al. (1969) concluded : 'The term'Histiocytosis X' is unnecessary and may lead to therapeutic errors.' KAUFMANet al. (1976) followed Lieberman's proposal, to speak of unifocal eosinophilic granuloma if only bone was involved and of multifocal eosinophilic granuloma when osseous and nonosseous structures were involved. BAYER et al. (1972) determined the lipid spectrum and fatty acid content of lung and femur in two patients. They found the cholesterol deposit for 73,1 ~ esterified. Cholestanol is not mentioned. GIAMPALMO (1953) found in the literature 11 cases with cerebrospinal symptoms excluding diabetes insipidus. The clinical picture resembled multiple sclerosis. There is no report of hereditary cases. To improve differential diagnosis in future biopsies and autopsies, it still might be worthwhile to look at the cholestanol content of the deposits. B. Xanthomatosis and Hyperlipoproteinemia

In several comprehensive reports tuberous xanthomas are mentioned : BEAUMONTet al. (1970) ; VAN BOGAERT(1937) ; VAN 8OGAERT ( 1962 I and 11) ; FREDRICKSONet al. (1967-5 parts); FREDRICKSONand LEVY(1972); FREDRICKSON(1972); FREDRICKSON (1975); DE

258 HG. 4 Possible but not proven cases of cerebrotendinous cholestanolosis

AUTHORS

a) age at first examination b) age at death

15 33

47 51

25

sex

M

F

F

mental deterioration

+

+

cataract

21

tendon xanthomas a) achilles b) other

a b

a b

dysfunction cortico spinal tracts cerebellar signs a) speech b) ataxia

a b

+

+

+

+

xanthelasma skin atrophy a) muscles

b) tongue

5 53

41

F

F

M

+

+

1 l/4y

20

+

15 +

20 +

+

24

B) biopsy A) autopsy before discovery cholestanol

+ A

42

M

M

F

F

M

27

+

q+ IQ 38

+ +

27,5 +

48 48

27

+

12/3y +

+ +

+

+

+

+

+

39

O

+ +

+

+

+

48

+

A

A

B

B

A

B

÷

cholesterol in serum

O

other signs

epilepsy

+ : mentioned as positive finding, mentioned as absent, blank space: not mentioned

47

+

hypaesthesia

--:

68 39

20 a b

29

O

O VIII, IX, X

O

021

O abdominal pains

O

cholestanol negative

259 GENNES et al. ( 1973 I and 1973 1I); GLUECKet al. (1973); GOLDSTEINet al. (1973); HARLAN et al. (1966); HEIBERG (1975, 1 and II); HESSEL et al. (1976); KHACHADURIAN and UTHMAN (1973); LEHMANN and LINES (1972); MIETTINENand ARDA (1973); MOTULSKY (1976); RAJASURIYA et al. (1960); RIEKIND (1973); ROSS and GLOMSET0976-6 parts); and of WIENKER et al. (1976). Especially tendinous xanthomas are mentioned as occurring in hyper-betalipoproteinemia. In the homozygote patient, tendon xanthomas appear already before the age of l0 years. Somewhat similar tubero-eruptive lesions appear in Types III and IV. Eruptive xanthomas indicate severe hyperglycideremia (Types I or V). Planar xanthomas in the palms of the hands occur in Types III and the homozygotes for Type II. Cholestanol is not mentioned in any of these reports. The possibility of cerebrotendinous cholesterolosis without cholestanolosis is discussed in E. C. The cerebrotendinous cholestanolosis

Since the original communication of VAN BOGAERT et al. (1937), and before the discovery of cholestanol by MENKESet al. (1968) and SCHIMSCHOCKet al. (1968), several patients with cerebrotendinous cholesterolosis were described by GUILLA|N et al. (1942), VINDITTI(1950), GIAMPALMO(1950), JERVIS(1957), STEINand CZUCZWAR(1959), RAJASURIYA et al. (1960), ORTlZ DE ZARATE (1962) and GALIZIOLI(1967). Later several, authors considered these as genuine ones. The judgement of the pathologist may have more weight than the clinician's, but for the moment the last word seems to be to the biochemist and histochemist. Fig. 4 gives a synopsis of the more or less probable but not proven cases of C. T. Ch.. Jervis's patient (1957) might have had a different disease. A synopsis of the patients, with an increase of cholestanol in bloodserum, material of biopsy - or autopsy, is given in Fig. 5. The patients, which have not yet been mentioned were described by: HARLAN and STILL (1968), SWANSON (1968), SALEN (1971), SALEN and POLITO (1972), SALEN and GRUNDY (1973), SETOGUCHI et al. (1974), DE VLEESCHOUWER et al. (1969), VAN BOGAERT et al. (1969), DERBY et al. (1970), PASTERSHANK et al. (1974), FARPOUR and MAHLOUDJ! (1975), SCHREINERet al. (1975). Several of these reports are about the same patients. HAVE et al. (1976) give fine pictures of the cataracts of two patients. They mention the biochemical tests needed for the diagnosis of C . T . C h . , but it is not stated, that these were performed. The age of first examination of the proven cases of C . T . C h . ranges from 19 to 58 years, the age at death from 37 to 60 years. The need for the demonstration of an increase of cholestanol in serum or biopsy becomes even more clear since the description of: D. X a n t h o m a t o s i s and Betha-Sitosterolemia

BHATTACHARYYA and CONNOR (1974) reported two sisters, which showed tendon xanthomas from the age of 8 years and no other signs at 22 and 20 years of age. They showed high plasmalevels of plant sterols: Betha-sitosterol, campesterol and stigmasterol. (Fig. 6.) The absorption of Betha-sitosterol was increased. Cholestanol was

260 FIC. 5. P r o v e n cases o f c e r e b r o t e n d i n o u s c h o l e s t a n o l o s i s

AUTHORS

~,

a) age at first e x a m i n a t i o n b) a g e at d e a t h

z-

~

~

~a---

35 40

55

58 60

57

29

34

25

23

21

49

37

sex

M

F

M

F

M

F

M

F

M

F

M

mental deterioration

12

10

+

+

18 m.

retardation + +

+

+

cataract

24

20

30

24

32

+

+

+

--

a b

+ 28

q-

I0

+

15 19

14 +

+ +

+

31 --

d y s f u n c t i o n c o r t i c o spinal tracts

34

+

+

+

+

cerebellar signs

17 17 17

30

+

+

tendon xanthomas a) achilles b) o t h e r

b) ataxia

a) speech

c) gait

a b

~

a

b c

h.ypaesthesia a t r o p h y muscles a) h a n d b) legs c) t o n g u e

13 +

+

+

+

+

a b c

+ + +

+ +

+ +

0

+

®

+ + ~

0

0

0 +

cardiovascular disturbances

54

B) b i o p s y w i t h i n c r e a s e d c h o l e s t a n o l A) a u t o p s y

A

a b

A

A

---

+

q-

B

-

EEG

hA

A

dar skil EMG denervation

steroid hormone pathology

0 +

+

A

23

+ +

c h o l e s t a n o l in s e r u m

o t h e r signs

+

+

cholesterol in s e r u m

a) x a n t h e l a s m a b) o t h e r x a n t h o m a s o f the skin

+

dys mi~

+ cloni velum

cloni velum

lichen plana pulmonary noduli

thy itis

261



40

~

~-

28

47

49

M

F

F

+

+

+

~

-

23

14

38

32

F

M

F

F

F

+

4

37 F

-

+

13

+

+

20 +

+ +

29

+

+

+

+

+

+

+

42

M

M

"1940 27

"1944 25

M

M

+ IQ

+ 1Q

75

73

15

10

+

+

6

6

22 + +

32

37

'1950 19 M mental retardation

27

30

25

+

18

32

-

+

27

31

17

rb

27 27

+ 25

17

+

27

+

O

O

10,64 14,36 mgr % m g r %

. .

+ +

O

O

O

O

O

O

O

O

4,± 0,50

3,2 40,24

1,8 40,35

2,Smgr 1,2mgr 100ml

2,67 mgr%

B

B before cholestanol

+

18 A

+

~- normal

+

theta theta delta delta activity activity

bilateral + slow waves

+

+

+

diarrhoea

psoriasis

+

amenor- amenor- diarrhoea rhoea rhoea

diarrhoea

O

262 not found. The patients were young and no predictions can be made as to the possibility of cerebrospinal signs at a later age.

C2Hs

HO Cholesterol (C~,H.O) mol. wt. 386.6

:;-Sitosterol (C,H,,O) tool. wt. 414.7

Campesterol (C~.H,.O) Stigrnasterol (C,.H.O) tool. wt. 400.7 rnoL wt. 412.7 THE CHEMICAL STRUCTURES OF CHOLESTEROL AND PLANT STEROLS

Fig. 6

E. Possible cerebrotendinous cholesterolosis without cholestanolosis

This is postulated by us as a hypothetical group. In so far as quantitation ofcholestanol is reliable, the patient of IWABUCHI et al. (1974) might be an example. The maternal aunt V.E. of VAN BOGAERa"S patients (1937-2), was for many years considered as having the same disease as her nephews (EPSTEIN and KRE1TNER, 1940). In 1969 PHILIPPART and VAN BOGAERT wrote after the autopsy: 'Hypercholesteremia can be associated with tendinous xanthomas and pseudosystemized central nervous system involvement...'. We examined the above-mentioned reports on xanthomatoses and hyperlipoproteinemia and did not find any relevant patients, neither in the familial studies of GENNES et al. (1973), GLUEC~ et al. (1973) and of HARLAN et al. (1966). Cerebrovascular accidents in hypercholesteremia are considered rare in several reports, but GENNES et al. (1973) found them 120 times in 250 cases. Some of these might lead to formation of cerebrospinal xanthomas. F. Spinal cholesterolosis

This was described by THlEBAUT(1942). The patient showed hypercholesteremia, progressive paraplegia and tendon xanthomas. There was no pathological confirmation. VAN BOGAERT(1962, 1965), reported the autopsy of a patient before the time ofcholestanol. WOL~AN (1976) considers it possible that the process, and its peculiar localization in the spinal cord, result from local factors in hyperlipidemic states, such as hemorrhage and infarction. He considers further studies necessary, as the syndrome might be a variant of cerebrotendinous cholestanolosis.

263

G. Cholesterolosis of the choroidplexus GIAMPALMO(1953) considered this to be more of pathologic anatomic than of clinical interest. WOLMAN (1976) mentions several patients with clinical signs. Examination of the cholestanol content is not reported.

H. Lipidosis with nervous tissue involvement FREDRICKSON (1968) and LOWENTHALand ZEMAN (1968) give a classification of these disease entities.

If. DISORDERS W I T H S E C U N D A R Y A P P E A R A N C E OF XANTHOMAS

A. Symptomatic forms of xanthomas and cholesterolosis These are seen in several internal diseases as hypothyroidy, hepatogenic disease and diabetes. The neurological disturbances will be a mixture of peripheral neuropathy and cerebrovascular affection, but might show superficial resemblance to C.T. Ch.

B. Xanthomatous transformation in meningiomas and neurinomas This has been described by RUSSEL and RUBINSTEIN(1971) in angioblastic and other types of meningiomas. They found it of c o m m o n occurrence in intracranial neurinomas.

C. Xanthomatous changes in demyelinating processes WOLMAN (1976) mentions this group and the following one:

D. Xanthomatous changes in systemic reticuloses

O P H T H A L M O L O G I C SIGNS IN C.T. CHOLESTANOLOSIS :

Xanthelasmata." These are mentioned twice in our synopsis and were absent in our own cases.

Corneal Arcus It seems that corneal arcus, which is an important sign in hyperlipoproteinemias and hyperglycideremias, is not found in C.T.Ch. Corneal arcus is twice mentioned as being absent, and was not found in our own patients.

Cataracts Bilateral cataracts are so c o m m o n that VlNDITTI(1950) proposed to speak of cerebrooculo-tendinous xanthomatosis. They are mentioned in 19 of the 26 proven cases. They may start in patients as young as I0 years of age(FARPOUR and MAHLOUDJI 1975);

264 with 'spotted cataracts in the anterior and posterior parts of the ventricular ( = lenticular?) cortex (outside the optical zone)', (SCHREINERet al. 1975). They are juvenile cataracts developing into cataracta corticalis posterior and anterior with radial stripes. In FARPOUR and MAHLOUDJI (1975) patient I and VAN BOGAERT'S (1937) patient I as zonular cataracts. The progression may vary. Our patient F. born 1950, (F II, 12) showed no cataracts in 1970, on 15-09-1975 he showed in mydriasis: lenses not clear, over the total field opacities, sometimes like a fine coerulea, sometimes combined to form small clouds, or rods, OD opacities in anterior and posterior cortex, OS only in anterior cortex, at both sides spoke formation in the lenses. The two patients G. and T. had been operated upon for cataract. The healthy brother L. F II, 3 showed in both lenses an infinity of small dots, many with a metallic aspect. As he had a normal cholestanol content of his serum and showed no aberrations, this might be a sign that he is a heterozygous carrier. Cholestanol

The work of MENgESet al. (1968) and SCHIMSCHOCKet al. (1968) has focussed attention on cholestanol in cerebrotendinous cholestanolosis. WERBIN et al. (1962) had brought evidence for the conversion of cholesterol to 5 alpha-cholestan-3 betha-ol (cholestanol) in the intact guinea pig. SHEFERet al. (1966) found a sequence of reaction products: cholesterol ~ cholestenone (4 cholesten-3-one) -> cholestanone (5 alpha cholestan-3one) ~ cholestanol. (Fig. 7.)

R (R=C.H~,) CHOLETTERO L HO Cholesterol

~ O

,

I

Cholestenon~ 0

Biochemical conversion

CHOLESTANOL

~

Cholestanone

Cholestanol

Fig. 7

MUCKENHAUSENet al. (1969) and DERBYet al. (1970) studied the brain of a patient with cerebrotendinous cholestanolosis. Three years before his death, 1,4- 14C-cholesterol was injected by the group of GARDNER-MEDWIN et al. (1971). They concluded that cholesterol turnover was normal, that little or no cholesterol was converted to serum cholestanol and that there is a deficient mechanism for removal of cholestanol from the brain, resulting in an increase of 200 ~o of the normal small content of cholestanol.

265 The studies of SALEN (1971), SALEN and POLITO (1972), SALEN and GRtJNOV (1973), SETOGUCHXet al. (1974), SHEFERet al. (1975), BJt~RKHEMand KALMAR (1974) resulted findings of abnormalities of sterol and bile acid metabolism in patients with C . T . Ch. a. elevated concentrations of cholesterol and cholestanol in tissues. b. greatly increased rates of cholesterol and cholestanol synthesis. c. bile acid production approximately 50 ~o below normal. d. detection of bile alcohols in the bile and isolation of substantial amounts from the feces, indicating a relative impairment in the degradation of the cholesterol side chain. The abnormally high activities of the rate controlling enzymes of bile acid synthesis can be ascribed to a failure of the bile alcohols to exert negative feedback controls on these enzymes. ISHIKAWA et al. (1976) stressed the difficulties of the quantitation of cholestanol, because minute quantities of cholestanol are present in plasma and tissues, with the exception of the large increase in C.T.Ch.. Cholestanol has been identified in human and atherosclerotic lesions. They fi.nd that their analytic method might have utility as regards to the atherosclerosis, and in the broad range of hyperlipoproteinemias where alterations in cholestanol metabolism might contribute additively to atherosclerotic potential. Genetics

The patients of VAN BOGAERTet al. (1937, 1969) were paternal cousins. SCmMSCIqOCK et al. (1968) write 'Our family, in which two of five siblings had the disease, has a clear history of consanguinity, in that the parents were first cousins'. DE VLEESCHAUWER et al. (1969) found two of three siblings diseased. VASTERSHANKet al. (1974): Three sisters, products of a consanguinous marriage were affected. FARVOUR et al. (1975) found one boy and one girl affected in a sibship of four males and three females. The parents were first cousins. In our family with three diseased children in a sibship of twelve, the parents had the same rather rare name and the ascendants lived in the 17th century in the same village. Consanguinity could not be proven. It may be concluded that C.T.Ch. shows an autosomal recessive type of inheritance. This may be a help in differentiating the disease against the xanthomatosis in hyperlipoproteinemias as the most relevant types show an autosomal dominant inheritance. C.T.Ch. shows no sex difference. The proven patients comprise 13 females and 13 males. The Karyotype of our patient G. F II, 4 was found normal: 46, XY. We looked for a linkage of the genetical disease with H.L.A. The following picture emerged : Conclusion after calculation of the Lod scores:

The material is too small for definitive pronouncements. When a recessive inheritance is taken for granted, there is no reason to assume a linkage with H.L.A. ; when an incomplete penetrance of a dominant factor, or a polygenous heredity are considered,

266

P 1565

H. L.A. Typing

19-3-1895

A1 1A3 B8 B7

12-3-1904

A2 lAw19 Bw37 B14

1118 Fig. 8

there is occasion to pay special attention to the possibility of linkage to H.L.A. in a larger material of combined, future cases.

DISCUSSION

Cerebrotendinous cholestanolosis is a rare disease. In all probability it is one of the inborn errors of metabolism, which have been considered an experiment of nature. Therefore, the interest is justifiable, as the increased content of the probably toxic cholestanol leads to consequences which may throw new light on several related or other diseases. In the first place the problem of atherosclerosis. A vascular component in C.T.Ch. was brought forward by SCHNEIDER(1936). VAN BOGAERT(1937) found no arteriosclerosis in the large vessels of the brain of his patient, though it played a role in the writings of EPSTEINet al. (1937, 1940). In the pathophysiological considerations about arteriosclerosis and lipidoses of MEYER et al. 0972) and of ROSS and GLOMSET (1976-6 parts) cholestanol is not mentioned. That an atherosclerotic factor plays a role in C.T.Ch. may follow from the description of cardiovascular disturbances in: the patient of SCHIMSCHOCK et al. (1968), the first patient of DE VLEESCHAUWERet al. (1969), the patient of HUGHESet al. (1971) and our patient G. The determination of the cholestanol content is difficult, but there is reason to consider the part, played in the origin of atheromata in the arteries in C.T.Ch. and in the origin of atherosclerosis in general. In the second place the problem of xanthomatosis. The dermatological aspects can not be treated extensively. A comprehensive report of the older literature is given by THANNHAUSER(1950). WOLMAN(1976) gives a review of the neurological sides of the problem. Several of the dermatological features are mentioned in our paragraph on xanthomatosis and hyperlipoproteinemia. In C.T.Ch. xanthomas of the skin were found in VAN BOGAERT'S (1937) second patient and in the patient of SCHREI-

267 NER et al. (1975). Our patient T. showed psoriasis. For the understanding of the pathogenesis of xanthomas the work of WALTON et al. (1973) seems important. The results described, support the general hypothesis, that xanthomas in the hyperlipaproteinemic rabbit arise from the escape of lipoprotein-rich plasma from abnormally permeable vessels into the neighbouring connective tissues, with subsequent uptake of betha-lipoprotein by phagocytic cells. PAR~ER et al. (1970) showed that each lipid moiety, after having been deposited in the xanthomas, is metabolized at a different rate. Metabolism of cholesterol proceeds slower than normal and so the cholesterol content will increase. As cholestanol in C.T.Ch. seems not to be metabolized at all, this may also be an explanation for the increasing amount of this substance. In the third place, as seen in the paragraph on cholestanol the work of several investigators has clarified some of the pathways of cholesterol, cholestanol and bile acid metabolism. FIG. 9. Effect of cholestyramine and of cholestyramine -k clofibrate on serum cholestanol concentrations of IIA (Fredrickson) patients.

No cholestyramine

pat

1 2 3 4 5

cholesterol mg ~

cholestanol mg %

% of total sterol

442 479 351 454 391

1.4 1.8 1.6 1.2 1.8

0.33 0.38 0.45 0.27 0.46

1.8

0.38

5.4 3.1 1.8 2.3

1.12 0.75 0.43 0.55

3.1

0.71

1.4 1.6

0.40 0.39

1.5

0.40

mean

cholestyramhte (10-15 g/daily) pat

6 7 8 9

483 405 423 411

mean

combined treatment pat

10 !1 mean

366 416

Unexplained in C.T.Ch. are the increase in cholesterol synthesis and the abnormal steroid hormone excretion in two of the patients of Steiner et al. (1975) and in two of our patients G. and F.

268 THERAPY

There is no specific therapy forC.T.Ch. ; treatment is entirely speculative.We considered the possibility that cholesterol lowering drugs used in type II A hyperlipoproteinemia, might also lower cholestanol levels in blood. To get an impression of the possible benefit of hypercholesterolemic drugs, we measured the blood cholesterol-levels in some arbitrarely chosen hypercholesterolemic patients with and without drug therapy. The most effective drug is cholestyramine, often used in combination with clofibrate. Drug 1 Cholestyramine, a drug that drains the enterohepatic circulation of bile acids. Drug 2 Clofibrate, a drug that interferes with the metabolism of cholesterol. In the upper part of Fig. 9 some cholesterol and cholestanol levels are given for patients treated with 10-15 gr. cholestyramine a day for one or more years, in the course of which the cholesterol concentrations were lowered by 15-207o, and in the lower part patients for a long time on combined therapy. As can be seen from Fig. 8, this sample of hypercholesterolemic patients on cholestyramine treatment have higher, rather than lower cholestanol levels. The two patients on combined treatment had no lower cholesterol levels than the control group. Therefore, we did not have sufficient arguments to convince the patients to follow a cholestyramine or a combined therapy. However, from these results a question can be raised concerning the enhancement of cholestanol levels, up to levels found in C.T.Ch. under influence of cholestyramine therapy. After exceeding a critical level excessive deposition of sterols might start. Concerning the effect of cholestyramine on sterol deposition in human subjects, there are several papers reporting the regression of xanthomas, as a result of the solubilisation of sterols in the dermis. However, in a preliminary paper of KUDCHODKAR et al. (1975), concerning three abnormal reacting patients, was reported that therapy increased cholesterol deposition, while in 1 control patient a combined treatment ofcholestyramine and clofibrate seemed to prevent sterol deposition. As the levels of cholestanol concentration were not determined in that study, in relation with our findings, the question can be raised if cholestanol levels in bloodserum might influence the deposition or solubilisition rate of sterols in tissues and with that respect cholestyramine might be not as harmless as is often assumed. As far as therapy is concerned some other treatments might be considered : a. SALEN and GRUNDY (1973) showed that administration of 750 mgr/day of chenodeoxycholic acid in patients with C.T.Ch. resulted in a marked reduction in the synthesis of both cholesterol and cholestanol. Although noticeable improvement in the clinical syndrome may require prolonged treatment, the apparent normalization of neutral sterol production with chenodeoxycholic acid is encouraging. b. TORSVIKet al. (1975) saw an effect of intravenous hyperalimentation which substantially lowered plasma concentrations of cholesterol, L.D.L.P. and H.D.L.P.

269 C. THOMPSONet al. (1975) saw results with plasma exchange in familial hyperlipoproteinemia Type III in combination with cholestyramine and nicotinic acid. d. LUPIEN et al. (1976) removed plasma cholesterol and L.D.L. by extracorporeal interaction of heparine linked to agarose beads, in the presence of calciumions.

ACKNOWLEDGEMENTS

The authors would like to thank Prof. W. A. den Hartog Jager for data of the observations of patients G. and F. at Amsterdam, and Doctors C. Hagen, J. F. Mirandolle and J. A. van der Snoek for information about the recent observations of patient G. at Heerlen, Mrs. P. M. van den Berg-Loonen and L. E. Nijenhuis for their cooperation on the H. L. A. Typing, Dr. David Goodman for helping with the translation, Miss T. Boonders for laboratory work and Mrs. C. Wegbrans for typing the manuscript.

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